U.S. patent application number 12/878287 was filed with the patent office on 2011-03-24 for sodium channel blocker delivery system with scleral lens.
This patent application is currently assigned to Boston Foundation for Sight. Invention is credited to Perry ROSENTHAL.
Application Number | 20110071631 12/878287 |
Document ID | / |
Family ID | 43732788 |
Filed Date | 2011-03-24 |
United States Patent
Application |
20110071631 |
Kind Code |
A1 |
ROSENTHAL; Perry |
March 24, 2011 |
SODIUM CHANNEL BLOCKER DELIVERY SYSTEM WITH SCLERAL LENS
Abstract
A scleral lens is provided with a sodium channel blocker or a
sodium channel modulator disposed in the pre-corneal tear film
between the scleral lens and the cornea. This system can be used to
deliver sodium channel blockers or a sodium channel modulators not
currently used because of poor bioavailability. Methods of using
this sodium channel blocker delivery system or a sodium channel
modulator delivery system are also disclosed.
Inventors: |
ROSENTHAL; Perry; (Newton,
MA) |
Assignee: |
Boston Foundation for Sight
Needham
MA
|
Family ID: |
43732788 |
Appl. No.: |
12/878287 |
Filed: |
September 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61241090 |
Sep 10, 2009 |
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61243037 |
Sep 16, 2009 |
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Current U.S.
Class: |
623/6.62 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 47/30 20130101; A61F 2/145 20130101; A61K 31/4164 20130101;
A61K 31/135 20130101; A61K 9/0048 20130101; A61K 47/20 20130101;
A61K 31/445 20130101; G02C 7/04 20130101 |
Class at
Publication: |
623/6.62 |
International
Class: |
A61F 2/16 20060101
A61F002/16 |
Claims
1. A sodium channel modulator delivery system comprising: (a) a
scleral lens to be disposed on an eye of a patient, the scleral
lens comprising: an optic portion having a first curvature, and a
scleral portion having a second curvature, wherein: (i) the first
curvature is adapted to cover a cornea of the eye without
substantially touching the cornea; (ii) the second curvature is
adapted to contact a sclera of the eye without substantially
touching the cornea; and (iii) the optic portion and the scleral
portion intersect to form an angle less than 180 degrees measured
from the anterior side of the scleral lens, and (b) a sodium
channel modulator disposed on the posterior side of the lens.
2. The sodium channel modulator delivery system of claim 1, wherein
the sodium channel modulator is lacosamide.
3. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of less than or
equal to about 5% lacosamide.
4. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 0.0001%
to about 0.05% lacosamide.
5. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 0.0001%
to about 5.0% lacosamide.
6. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 0.05%
to about 1.0% lacosamide.
7. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 0.05%
lacosamide.
8. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 1.0%
lacosamide.
9. The sodium channel modulator delivery system of claim 2, wherein
the lacosamide is in a solution at a concentration of about 5%
lacosamide.
10. The sodium channel modulator delivery system of claim 2,
wherein the lacosamide is in a solution at a concentration of about
0.003% lacosamide.
11. A method of treating corneal neuropathic pain in the eye of a
patient, the method comprising the step of applying the sodium
channel modulator delivery system of claim 1 to the eye of a
patient suffering from corneal neuropathic pain.
12. The method of claim 11, wherein the sodium channel modulator is
administered to the eye, then the scleral lens is applied to the
eye.
13. The method of claim 11, wherein the sodium channel modulator is
added to the scleral lens, then the scleral lens is applied to the
eye.
14. The method of claim 11, wherein the sodium channel modulator is
lacosamide.
15. The method of claim 14, wherein the lacosamide is at a
concentration of less than or equal to about 5% lacosamide.
16. The method of claim 14, wherein the lacosamide is at a
concentration of about 0.001% to about 5.0% lacosamide.
17. The method of claim 14, wherein the lacosamide is at a
concentration of about 0.5% to about 1.0% lacosamide.
18. The method of claim 14, wherein the lacosamide is at a
concentration of about 0.5% lacosamide.
19. The method of claim 14, wherein the lacosamide is at a
concentration of about 1.0% lacosamide.
20. The method of claim 14, wherein the lacosamide is at a
concentration of about 0.003% lacosamide.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Application Ser. No. 61/241,090 filed Sep. 10, 2009,
and U.S. Provisional Application Ser. No. 61/243,037 filed Sep. 16,
2009, the disclosures of each of which is incorporated herein by
reference in its entirety.
TECHNICAL FIELD
[0002] This disclosure relates generally to a delivery system for
retaining a sodium channel blocker at the surface of an eye when a
scleral lens is disposed on the eye; a method of using a scleral
lens to retain a sodium channel blocker at the surface of the eye;
and methods for treating conditions and diseases of the eye.
BACKGROUND
[0003] Eye diseases and conditions can be treated with topical
agents, such as drops or ointments, which use direct absorption to
reach therapeutic drug levels at the target tissue. Topical
application is especially useful for the cornea, which has
virtually no blood supply and is easily accessible for topical
application. When drugs are applied topically in the form of drops
or ointment to the cornea, however, the drug solution rapidly
disperses into the tear film and flows into the tear drainage
system, thereby reducing bioavailability. Non-limiting examples of
factors affecting the bioavailability of a drug (i.e., drug levels)
in the cornea and to the anterior chamber of the eye include the
duration of the drug's effective concentration at the surface of
the cornea, and the drug's ability to be absorbed into the corneal
tissue.
[0004] Delivering medications in the form of eye drops can have two
main disadvantages. First, the concentration of the drug can
rapidly fall below therapeutic levels, potentially requiring
frequent applications of the drug. Second, high concentrations of
the drug may be necessary to achieve adequate penetration into the
eye because of the drug's brief contact time with the eye, and
these high concentrations may be toxic.
[0005] An existing method of delivering a drug to the cornea
involves dehydrating a soft contact lens, then soaking the lens in
a solution of the drug. This method provides an initial burst
release of the drug followed by continuous decline in the amount of
drug at the cornea. This leads to limited bioavailability of the
drug after the initial burst release.
[0006] Another method of delivering a drug to the cornea involves
soaking a collagen shield in a solution of the drug. These collagen
shields are opaque and must be worn in a recess under the lids.
Because the impregnated drug is carried to the corneal surface by
the tears, its bioavailability is limited in dry eye disease, a
common condition in eyes with neuropathic pain.
SUMMARY
[0007] A scleral lens rests on the sclera of the eye without
substantially touching the cornea. A scleral lens defines a "fluid
compartment" between the inner surface of the vaulted area and the
cornea. This fluid compartment is also referred to as a fluid
reservoir, a pre-corneal tear film, an expanded pre-corneal tear
film, or as a supplemented pre-corneal tear film.
[0008] The scleral lens also provides a novel method of retaining a
drug at the corneal surface in the expanded pre-corneal tear film,
which is retained at the surface of the cornea by the scleral lens.
The drug is disposed on the back of the scleral lens. The drug may
be added to the fluid compartment of the scleral lens, which is
then inserted into the eye. Alternatively, the drug is administered
to the eye, then the scleral lens is inserted into the eye.
[0009] A scleral lens provides high bioavailability of drugs to the
relatively avascular cornea, and perhaps to the anterior chamber of
the eye, without the potential risks of systemic spillover or the
requirement of frequent administration. The scleral lens retains
the drug at the cornea, and thus can better maintain a controlled
concentration of the drug at the site of administration compared to
other known methods. This approach can require less frequent dosing
regimens, which reduces noncompliance. This also enables the use of
low, non-toxic concentrations of drug to be applied to the eye. The
scleral lens provides these benefits while keeping the cornea
oxygenated and allowing the patient to see, or even enhancing the
patient's vision.
[0010] In one aspect, the present disclosure relates to a sodium
channel blocker delivery system including a scleral lens to be
disposed on an eye of a patient, wherein the scleral lens includes
an optic portion having a first curvature, and a scleral portion
having a second curvature, wherein the first curvature is adapted
to cover a cornea of the eye without substantially touching the
cornea; the second curvature is adapted to contact a sclera of the
eye without substantially touching the cornea; and the optic
portion and the scleral portion intersect to form an angle less
than 180 degrees measured from the anterior side of the scleral
lens, and a sodium channel blocker disposed on the posterior side
of the lens.
[0011] In another aspect, the present disclosure relates to a
method of treating corneal neuropathic pain in the eye of a
patient, where the method includes administering a sub-anesthetic
concentration of a sodium channel blocker or a sodium channel
modulator to the eye; and applying a scleral lens to the eye, where
the scleral lens includes an optic portion having a first
curvature, and a scleral portion having a second curvature, wherein
the first curvature is adapted to cover a cornea of the eye without
substantially touching the cornea; the second curvature is adapted
to contact a sclera of the eye without substantially touching the
cornea; and the optic portion and the scleral portion intersect to
form an angle less than 180 degrees measured from the anterior side
of the scleral lens.
[0012] In another aspect, the present disclosure relates to a
method of retaining a sodium channel blocker or a sodium channel
modulator at the surface of the eye of a patient, where the method
includes administering a sub-anesthetic concentration of the sodium
channel blocker or the sodium channel modulator to the eye; and
applying a scleral lens to the eye, where the scleral lens includes
an optic portion having a first curvature, and a scleral portion
having a second curvature, wherein the first curvature is adapted
to cover a cornea of the eye without substantially touching the
cornea; the second curvature is adapted to contact a sclera of the
eye without substantially touching the cornea; and the optic
portion and the scleral portion intersect to form an angle less
than 180 degrees measured from the anterior side of the scleral
lens.
[0013] In some embodiments, the sodium channel blocker is a sodium
channel blocker anesthetic, tricyclic antidepressant or
antiepileptic. In other embodiments, the sodium channel blocker is
selected from the group consisting of bupivacaine, lidocaine,
proparacaine, tetracaine, ropivacaine, levobupivacaine, and
amitriptyline. In some embodiments, the sodium channel blocker is
in a solution at a concentration of about 0.04% to about 0.0005%,
or at a concentration of about 0.002% to about 0.001%. In other
embodiments, the sodium channel blocker is in a solution at a
concentration of about 0.05% to about 0.0005%, or at a
concentration of about 0.05% to about 0.001%.
[0014] In some embodiments, the sodium channel blocker is present
in a sub-anesthetic concentration. In some embodiments, the sodium
channel blocker is present in a sub-toxic concentration. In some
embodiments, the sodium channel blocker is present in a
therapeutically effective concentration.
[0015] In some embodiments, the scleral lens does not touch the
cornea of the eye. In some embodiments, the scleral portion of the
scleral lens defines at least one channel. In other embodiments,
the scleral lens defines at least one fenestration.
[0016] In some embodiments, the optic portion of the scleral lens
is optically corrective. In other embodiments, the optic portion of
the scleral lens is not optically corrective.
[0017] In some embodiments, the sodium channel blocker includes a
solution of about 0.0009% to about 0.0019% bupivacaine; or a
solution of about 0.0014% bupivacaine. In other embodiments, the
sodium channel blocker includes a solution of about 0.02% to about
0.001% ropivacaine; or a solution of about 30 .mu.g/mL to about 200
.mu.g/mL ropivacaine.
[0018] In some embodiments, the sodium channel modulator includes a
solution of about 0.05% to about 0.001% lacosamide; or a solution
of about 0.003% lacosamide. In some embodiments, the sodium channel
blocker includes a solution of less than or equal to about 0.5%
lacosamide; a solution of less than or equal to about 1%
lacosamide; a solution of less than or equal to about 5%
lacosamide; or a solution of about 0.001% to about 5%
lacosamide.
[0019] In some embodiments, the sodium channel modulator is
lacosamide administered to the eye in the form of eye drops,
ointment, gel, or slow release polymer. In some embodiments, the
sodium channel modulator includes a solution of less than or equal
to about 0.5% lacosamide; a solution of less than or equal to about
1% lacosamide; or a solution of less than or equal to about 5%
lacosamide. In some embodiments, the sodium channel modulator
includes a solution of about 0.5% to about 1% lacosamide; a
solution of less than or equal to about 5% lacosamide; or a
solution of about 0.001% to about 5% lacosamide.
[0020] In some embodiments, the sodium channel blocker or the
sodium channel modulator is administered to the eye, then the
scleral lens is applied to the eye. In other embodiments, the
sodium channel blocker is added to the scleral lens, then the
scleral lens is applied to the eye.
[0021] In some embodiments, the patient suffers from corneal
neuropathic pain.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] In the Drawings:
[0023] FIG. 1 is a perspective view of an eye with a scleral lens
with scalloped channels.
[0024] FIG. 2 is a cross-sectional view taken along line 2-2 of
FIG. 1.
DETAILED DESCRIPTION
[0025] The present disclosure relates to a discovery that
sub-anesthetic concentrations of a sodium channel blocker or a
sodium channel modulator may treat corneal neuropathic pain when
delivered to the eye using a scleral lens. In some embodiments, the
sodium channel blocker is a sodium channel blocker anesthetic.
These sub-anesthetic concentrations of sodium channel blocker are
also sub-toxic, and therefore allow for continued use of the sodium
channel blocker in the eye. Without being bound by any particular
theory, it is believed that the scleral lens improves retention of
the sodium channel blocker or the sodium channel modulator at the
surface of the eye, thereby improving the bioavailability of the
sodium channel blocker or the sodium channel modulator.
[0026] The present disclosure provides a sodium channel blocker
delivery system including a scleral lens and a sodium channel
blocker (or a sodium channel modulator) disposed on the posterior
side of the scleral lens. The sodium channel blocker (or sodium
channel modulator) is retained in the expanded pre-corneal tear
film defined as the area between the scleral lens and the cornea
(i.e., the fluid compartment).
[0027] The present disclosure also provides a method of increasing
the bioavailability of a sodium channel blocker or a sodium channel
modulator delivered to the surface of the eye using a scleral lens,
whereby a solution of a sodium channel blocker or a sodium channel
modulator is added to the fluid compartment.
[0028] The present disclosure also provides a method of retaining a
sodium channel blocker or a sodium channel modulator at the surface
of the eye using a scleral lens, whereby a solution of a sodium
channel blocker or a sodium channel modulator is added to the fluid
compartment.
[0029] 1. Scleral Lens
[0030] A scleral lens is described in U.S. Pat. No. 7,591,566,
which is incorporated herein by reference in its entirety. A
scleral lens is also described in U.S. Pat. No. 7,695,135, which is
incorporated herein by reference in its entirety. A method of
making a scleral lens is described in U.S. Pat. No. 5,452,031,
which is incorporated herein by reference in its entirety.
[0031] A scleral lens is a rigid, gas permeable contact lens that
rests on the sclera of the eye; some scleral contact lenses rest on
the peripheral surface of the cornea while others do not touch the
cornea at all. The scleral lens defines a compartment of fluid
between the inner surface of the scleral lens and the cornea,
referred to herein as the "fluid compartment." The portion of the
scleral lens that contacts the sclera is referred to as the
"scleral portion" of the scleral lens, or as the "haptic." The
portion of the scleral lens that covers the cornea is called the
"optic portion" of the scleral lens. The optic portion may
optionally be corrective. The greatest distance between the surface
of the cornea and the posterior side of the optic portion is at
least about 30 microns. As used herein, the posterior side of the
scleral lens is the side that is disposed on the eye.
[0032] Referring to FIGS. 1 and 2, the eye has an anterior portion
10. As shown in FIG. 2, the anterior portion 10 of the eye has a
sclera 12 and a cornea 13. The sclera 12 is the white part of the
eye.
[0033] Referring to FIGS. 1 and 2, a scleral lens 1 rests on the
anterior portion 10 of an eye. Scleral lens 1 is a rigid lens that
rests on the sclera 12 of the eye but either does not touch the
cornea 13 or just touches a peripheral surface of cornea 13. The
eye and scleral lens 1 define a fluid compartment 4 between the
inner surface of the scleral lens and the cornea 13.
[0034] The portion of the scleral lens 1 that touches the sclera 12
is referred to as the scleral portion 3 of the scleral lens, or as
the "haptic." The portion of the scleral lens 1 that covers the
cornea 13 is referred to here as the optic portion 5 of the scleral
lens. The optic portion 5 may optionally be corrective. The
greatest distance between the surface of the cornea 13 and the
posterior side of the optic portion is typically at least 30
microns. As used herein, the posterior side of the scleral lens 1
is the side that is disposed on the eye. The anterior side of the
scleral lens 1 is the side facing away from the eye when the
scleral lens is disposed on the eye.
[0035] As shown in FIG. 2, the curvature of scleral portion 3 is
not the same as the curvature of optic portion 5. This difference
in curvature causes the optic portion 5 to protrude away from the
anterior portion 10 of the eye when disposed on the eye, while the
scleral portion 3 conforms to the curvature of the sclera 12, as
shown in FIG. 2. The curvature of the optic portion 5 is referred
to herein as the first curvature. The curvature of the scleral
portion 3 is referred to herein as the second curvature.
[0036] The first and second curvatures may be portions of spheres
with constant radii. Alternatively, the first and second curvatures
are not portions of spheres, so that the first and second
curvatures do not have constant radii. Alternatively, the first and
second curvatures are adapted based on the topography of the cornea
or the sclera of an eye. Scleral lenses with curvatures that do not
have constant radii, or that are adapted based on the topography of
the cornea or the sclera of an eye, are described at column 4, line
30 through column 9, line 22 in U.S. Pat. No. 5,452,031, the
entirety of which patent is incorporated herein by reference.
[0037] FIG. 2 shows that the intersection of the optic portion 5
and the scleral portion 3 forms an angle, angle A. Angle A may be
uniform throughout the intersection of the optic portion 5 and the
scleral portion 3. Alternatively, angle A may vary throughout the
intersection of the optic portion 5 and the scleral portion 3.
Angle A is less than 180 degrees.
[0038] In some embodiments, the posterior side of the scleral
portion 3 optionally defines one or more channels 6 that extend
generally radially from an outside rim 7 of the scleral lens to an
inner rim 8 of the scleral portion. These optional channels are
shown in FIGS. 1 and 2. In some embodiments, as shown in FIG. 1,
the edge of the channel 6 optionally defines a scallop 2 where the
channel 6 meets the outside rim 7 of the scleral lens 1.
[0039] In some embodiments, the scleral lens optionally defines one
or more fenestrations. As used herein, the term fenestration refers
to an opening defined by the scleral lens that allows for fluid
and/or gaseous communication between the fluid compartment 4 and
the outside of the scleral lens. In another embodiment, the optic
portion of the scleral lens defines a circumferential fenestrated
channel. A non-limiting example of such a scleral lens is described
in U.S. Pat. No. 7,695,135, which is incorporated herein by
reference in its entirety.
[0040] Another non-limiting example of a scleral lens suitable for
use with the present sodium channel blocker delivery system is the
Boston Ocular Surface Prosthesis (BOS-P) (Boston Foundation for
Sight, Needham, Mass.).
[0041] 2. Sodium Channel Blockers
[0042] Corneal neuropathic pain is associated with abnormal
activity of the pain sensors/generators located on the surface of
the cornea below the tear/mucin layer. The sensory nerve endings
that identify noxious stimulus and convert it into a electrical
pain signal are called nociceptors.
[0043] Sodium channel blockers, such as local sodium channel
blocker anesthetics, function by blocking a key step in the
transduction of noxious stimulation into electrical activity: the
opening of sodium ion channels in the membrane of nociceptors. The
resulting inflow of positively charged sodium ions creates an
electrical current which if adequate, results in the generation of
action potentials that are conducted to the central nervous system
where it is perceived as pain. Sodium channel blockers inactivate
sodium ion channels, thereby blocking the transduction of noxious
stimulus into a pain signal.
[0044] Sodium channel blockers may be used to treat pain throughout
the body and have been administered by various routes, including
topical delivery. Although sodium channel blockers can be
administered by the ocular route, sodium channel blockers can be
toxic to the cornea and chronic use can cause permanent corneal
damage. Risco and Millar, Ophthalmology 99(4):628-633 (1992); Varga
et al., Cornea 16(4):424-429 (1997), both of which are incorporated
herein by reference in their entirety. Accordingly, sodium channel
blockers are typically administered to the eye only for diagnostic
or short surgical procedures.
[0045] Bupivacaine is a sodium channel blocker that may be
administered to the eye for limited periods of time. Bupivacaine is
used as a topical corneal anesthetic at concentrations of about
0.5% to about 0.75%. A 1 mg dose of bupivacaine, formulated as eye
drops and in a soluble hyaluronic acid ophthalmic insert, was also
used as an anesthetic during cataract surgery. Mahe et al., Br. J.
Clin. Pharmacol. 59(2):200-226 (2005), which is incorporated herein
by reference in its entirety. Proparacaine at a 0.05% concentration
has been used to reduce pain after photorefractive keratectomy.
Shahinian et al., Ophthalmology 104(8):1327-1332 (1991), which is
incorporated herein by reference in its entirety. This dosage was
found to be non-anesthetic, non-toxic, and safe for at least one
week of use.
[0046] Non-limiting examples of sodium channel blockers suitable
for use with the present sodium channel blocker delivery system
include tricyclic antidepressants, bupivacaine, lidocaine,
proparacaine, tetracaine, ropivacaine, levobupivacaine, flecainide,
carbamazepine, and amitriptyline.
[0047] As used herein, the phrase "therapeutic effect" is a desired
consequence of a medical treatment. As used herein, the phrases
"therapeutically effective dose," "therapeutically effective
amount," and "therapeutically effective concentration" refer to the
dose required to achieve a therapeutic effect. "Therapeutically
effective dose," "therapeutically effective amount," and
"therapeutically effective concentration" may be used
interchangeably.
[0048] As used herein, the phrases "anesthetic dose" and
"anesthetic concentration" refer to a dose of a sodium channel
blocker anesthetic that is sufficient to achieve an anesthetic
effect. "Anesthetic dose" and "anesthetic concentration" may be
used interchangeably. The anesthetic dose of bupivacaine is 0.5% to
0.75% when formulated for use as eye drops alone (i.e., when not
formulated for use in the present sodium channel blocker delivery
system). As used herein, an "anesthetic effect" is the elimination
of sensation.
[0049] As used herein, the phrase "sub-hypoesthetic dose" refers to
a dose of a sodium channel blocker or a sodium channel modulator
that does not depress corneal sensation. The sub-hypoesthetic dose
for a sodium channel blocker or a sodium channel modulator may vary
between patients. The sub-hypoesthetic dose of a sodium channel
blocker or a sodium channel modulator may vary between patients.
The sub-hypoesthetic dose of a sodium channel blocker or a sodium
channel modulator can be determined for an individual patient by
selecting a higher starting concentration and gradually reducing
the concentration via titration until reaching a sub-hypoesthetic
dose as determined by a contact and non-contact esthesiometer. A
non-limiting example of a method of determining corneal sensitivity
is Cochet-Bonnet aesthesiometry.
[0050] As used herein, the phrases "sub-anesthetic dose" and
"sub-anesthetic concentration" refer to a dose of a sodium channel
blocker or a sodium channel modulator or a sodium channel modulator
that is lower than the anesthetic dose. "Sub-anesthetic dose" and
"sub-anesthetic concentration" may be used interchangeably. The
sub-anesthetic dose of a sodium channel blocker or a sodium channel
modulator may vary between patients. The sub-anesthetic dose of a
sodium channel blocker or a sodium channel modulator can be
determined for an individual patient by selecting a higher starting
concentration and gradually reducing the concentration via
titration until reaching a sub-anesthetic dose as determined by a
contact and non-contact esthesiometer. A non-limiting example of a
starting concentration of a sodium channel blocker or a sodium
channel modulator is about 0.02%. In some embodiments, the
concentration of the sodium channel blocker or a sodium channel
modulator may be titrated down to a concentration that avoids any
depression of corneal sensitivity. A non-limiting example of a
method of determining corneal sensitivity is Cochet-Bonnet
aesthesiometry.
[0051] As used herein, the phrases "toxic concentration," "toxic
dose," and "toxic amount" refer to a dose of a compound that causes
cellular damage to the tissue to which it is applied. The phrases
"toxic concentration," "toxic dose," and "toxic amount" also refer
to a dose that causes unwanted side effects. The phrases "toxic
concentration," "toxic dose," and "toxic amount" may be used
interchangeably.
[0052] The phrases "sub-toxic concentration," "sub-toxic dose," and
"sub-toxic amount" refer to a dose of a compound that does not
cause cellular damage to the tissue to which it is applied, or that
does not cause unwanted side effects. The phrases "sub-toxic
concentration," "sub-toxic dose," and "sub-toxic amount" may be
used interchangeably.
[0053] 3. Scleral Lens/Sodium Channel Blocker Combination; Scleral
Lens/Sodium Channel Modulator Combination
[0054] A scleral lens can be used as a sodium channel blocker
delivery system (or as a sodium channel modulator) by providing a
sodium channel blocker or a sodium channel modulator in the fluid
compartment, thus keeping the sodium channel blocker or sodium
channel modulator in contact with the surface of the cornea. The
scleral lens/sodium channel blocker combination is referred to
herein as the "sodium channel blocker delivery system." The scleral
lens/sodium channel modulator combination is referred to herein as
the "sodium channel modulator delivery system." The sodium channel
blocker delivery system (or sodium channel modulator delivery
system) may be used in a method of treating corneal neuropathic
pain, where the sodium channel blocker delivery system (or sodium
channel modulator delivery system) is applied to the eye of a
patient. The sodium channel blocker delivery system (or sodium
channel modulator delivery system) may be used in a method of
retaining a sodium channel blocker (or sodium channel modulator) at
the surface of an eye of a patient, where the sodium channel
blocker delivery system (or sodium channel modulator delivery
system) is applied to the eye of a patient.
[0055] In some embodiments, a solution of the sodium channel
blocker or the sodium channel modulator is added to the posterior
side of the scleral lens, then the scleral lens is applied to the
patient's eye. In other embodiments, a solution of the sodium
channel blocker or the sodium channel modulator is administered to
the patient's eye, then the scleral lens is applied to the
patient's eye.
[0056] Surprisingly, sub-anesthetic concentrations of sodium
channel blocker (or sodium channel modulator) may be used in the
present sodium channel blocker delivery system (or sodium channel
modulator delivery system) to produce a therapeutic effect, e.g.,
to treat corneal neuropathic pain. Furthermore, the combination of
a sub-anesthetic concentration of a sodium channel blocker (or
sodium channel modulator) with a scleral lens can produce a
therapeutic effect, e.g., treat corneal neuropathic pain, while
retaining the treated eye's normal sense of touch.
[0057] Solutions containing about 0.04% to about 0.0005% of a
sodium channel blocker or sodium channel modulator may be used with
the sodium channel blocker delivery system (or sodium channel
modulator delivery system) of the present disclosure.
Alternatively, the sodium channel blocker delivery system (or
sodium channel modulator delivery system) includes a solution
containing about 0.002% to about 0.001% of a sodium channel blocker
(or sodium channel modulator). In some embodiments, the sodium
channel blocker delivery system includes a solution containing
about 0.0001% to about 0.05% of a sodium channel blocker. In some
embodiments, the sodium channel modulator delivery system includes
a solution containing about 0.001% to about 0.5% of a sodium
channel modulator. In some embodiments, the sodium channel blocker
delivery system (or sodium channel modulator delivery system)
includes a solution containing about 0.0019% to about 0.0009% of a
sodium channel blocker (or sodium channel modulator). In still
other embodiments, the sodium channel blocker delivery system (or
sodium channel modulator delivery system) includes a solution
containing about 0.0014% of a sodium channel blocker (or sodium
channel modulator). In other embodiments, the sodium channel
blocker delivery system (or sodium channel modulator delivery
system) includes a solution containing about 0.02% to about 0.0025%
of a sodium channel blocker (or sodium channel modulator).
[0058] In some embodiments, only one sodium channel blocker (or
sodium channel modulator) is used in the sodium channel blocker
delivery system (or sodium channel modulator delivery system) of
the present disclosure. In other embodiments, combinations of more
than one sodium channel blocker (or sodium channel modulators) are
used in the sodium channel blocker delivery system of the present
disclosure. In some embodiments, combinations of two, three, four,
five, six, seven, eight, nine, or ten different sodium channel
blockers (or sodium channel modulators) are used in the sodium
channel blocker delivery system of the present disclosure.
[0059] In one embodiment, the sodium channel blocker includes a
solution of about 0.0014% to about 0.001% bupivacaine. In another
embodiment, the sodium channel blocker includes a solution of about
0.0009% to about 0.0019% bupivacaine. In another embodiment, the
sodium channel blocker includes a solution of about 0.02% to about
0.0025% ropivacaine. In another embodiment, the sodium channel
blocker includes a solution of about 30 .mu.g/mL to about 200
.mu.g/mL ropivacaine.
[0060] In another embodiment, the sodium channel blocker includes a
solution containing about 0.0005%, about 0.001%, about 0.0015%,
about 0.002%, about 0.0025%, about 0.003%, about 0.0035%, about
0.004%, about 0.0045%, about 0.005%, about 0.0055%, about 0.006%,
about 0.0065%, about 0.007%, about 0.0075%, about 0.008%, about
0.0085%, about 0.009%, about 0.0095%, about 0.01%, about 0.02%,
about 0.03%, about 0.04%, or about 0.05% of a sodium channel
blocker.
[0061] The sodium channel blocker delivery system (or sodium
channel modulator delivery system) disclosed herein can provide
relief from corneal neuropathic pain within about 30 minutes of
applying the sodium channel blocker delivery system (or sodium
channel modulator delivery system) to an eye. In certain instances,
the sodium channel blocker delivery system (or sodium channel
modulator delivery system) may be used for a period of time ranging
from one day to every day for one year. In other instances, the
sodium channel blocker delivery system (or sodium channel modulator
delivery system) may be used every day for more than one year. In
some instances, the sodium channel blocker delivery system (or
sodium channel modulator delivery system) may be worn for a period
of time ranging from about one hour per day to all waking hours of
the day. In a non-limiting example, the sodium channel blocker
delivery system (or sodium channel modulator delivery system) may
be worn all waking hours of the day, every day for a year or
longer.
[0062] Solutions containing a sodium channel blocker (or sodium
channel modulator) for use in the present sodium channel blocker
delivery system (or sodium channel modulator delivery system) are
formulated to be suitable for ocular use. A non-limiting example of
such a solution is a solution including normal saline and a sodium
channel blocker (or sodium channel modulator).
[0063] Non-limiting examples of diseases or conditions that may be
treated using the sodium channel blocker delivery system (or sodium
channel modulator delivery system) of the present disclosure
include corneal neuropathic pain caused by cosmetic lid surgery,
Lasik surgery, Sjogren's syndrome and other autoimmune disorders,
dry eye, exposure to noxious fumes, exposure to ultraviolet B, and
exposure to ACCUTAINE.RTM. (isotretinoin). The terms "disease,"
"condition," and "disorder" are used interchangeably herein.
[0064] Additional pharmaceutically acceptable compounds or
excipients known to those of ordinary skill in the art may
optionally be used with the sodium channel blocker delivery system
(or sodium channel modulator delivery system) of the present
disclosure. For example, compounds that increase the absorption of
a sodium channel blocker (or sodium channel modulator) by the
cornea may be used. Non-limiting examples of compounds that
increase the absorption of a sodium channel blocker (or sodium
channel modulator) by the cornea include dimethyl sulfoxide
(DMSO).
[0065] The sodium channel blocker delivery system (or sodium
channel modulator delivery system) of the present disclosure may
also be used without any additional pharmaceutically acceptable
compounds or excipients.
[0066] 4. Sodium Channel Modulators
[0067] The instant disclosure also relates to a sodium channel
modulator delivery system. Sodium channel modulators are compounds
that enhance slow inactivation of voltage gated sodium channels. A
non-limiting example of a sodium channel modulator is lacosamide.
Lacosamide is a novel sodium channel modulator developed for the
management of epileptic seizures and diabetic neuropathy.
[0068] Lacosamide enhances slow inactivation of the sodium ion
channel blockers in the sensory nerve terminals (nociceptors), a
process that occurs over hundreds of milliseconds or longer.
Recovery can take as long. This is different than local anesthetics
in which the mechanism of action is prolonging fast inactivation.
The mechanism of local anesthetics is based on their ability to
delay the recovery of nociceptors from fast inactivation. It is
estimated that lacosamide inactivates voltage gated sodium channels
for a period of time 100 to 1,000 fold greater than local
anesthetics. (Errington et al., Mol. Pharmacol. 73(1):157-69
(2008), which is incorporated herein by reference in its entirety).
Therefore, lacosamide can provide a longer duration of action than
other sodium channel blockers.
[0069] Slow inactivation occurs preferentially in tonically active
nociceptors and is facilitated by prolonged depolarization.
Presumably, this phenomenon is a physiological mechanism for
dampening the hyperactivity of sensitized nociceptors.
Theoretically, a drug that facilitates the entry of hyperactive,
sensitized nociceptors into the slow inactivation state may be
effective in down-regulating preferentially abnormal nociceptive
activity responsible for corneal hyperalgesia and pain while
preserving the function of mechanoreceptors and normally
functioning nociceptors. Another advantage of a drug that enhances
slow but not fast inactivation is that it not blocking sodium
channels, it does not have local anesthetic properties. Lacosamide
has these properties.
[0070] Lacosamide has a selective effect on dysfunctional,
hyperactive voltage gated sodium channels (e.g., it acts only on
depolarized neurons and those that have been active for some time)
(Sheets et al., J. Pharmacol. Exp. Ther. 326(1):89-99 (2008), which
is incorporated herein by reference in its entirety). Lacosamide is
especially effective in targeting sodium channels involved in
sustained high frequency neuronal firing or those affected by
prolonged depolarization. These are typical characteristics of the
dysfunctional voltage-gated sodium channels responsible for
neuropathic pain. Moreover, slow inactivation can be expected to
have less anesthetic effect because it does not completely block
the sodium ion channels.
[0071] Without being bound to any particular theory, it is believed
that the effectiveness of sodium channel modulators in treating
corneal neuropathic pain is due to their ability to target
hyperactive nociceptors and ectopic firing sites without affecting
normal corneal sensitivity.
[0072] Lacosamide is water soluble and can be delivered to the
corneal surface in the form of eye drops (i.e., ophthalmic
solutions). Other non-limiting examples of lacosamide formulations
suitable for use in the present disclosure include ophthalmic
suspensions and ophthalmic ointments. Non-limiting examples of how
to make and use eye drops, ophthalmic suspensions, ophthalmic
ointments, and other ophthalmic preparations may be found in such
standard references as Gerald Hecht, Chapter 43: Ophthalmic
Preparations, in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY,
821-835 (A. R. Gennaro, ed., 20th edition, Lippincott Williams
& Wilkins, Philadelphia, Pa., 2000), which is incorporated
herein by reference in its entirety.
[0073] Lacosamide may be embedded in a slow release polymer which
is then positioned under an eyelid, or which is used to form a
contact lens. A non-limiting example of a slow release polymer
suitable for use with the present disclosure is nanofiber hydrogel
scaffolding. Lacosamide may also be delivered to the corneal
surface using the sodium channel modulator delivery system
described herein.
[0074] In some embodiments, lacosamide is the only drug used in the
sodium channel modulator delivery system of the present disclosure.
In other embodiments, lacosamide is used in combination with other
drugs in the sodium channel modulator delivery system (or sodium
channel blocker delivery system) of the present disclosure. In
still other embodiments, lacosamide is used in combination with at
least one sodium channel blocker in the sodium channel blocker
delivery system of the present disclosure. In yet other
embodiments, lacosamide is used in combination with one, two,
three, four, five, six, seven, eight, nine, or ten sodium channel
blockers in the sodium channel modulator delivery system (or sodium
channel blocker delivery system) of the present disclosure.
[0075] Solutions containing less than or equal to about 5%
lacosamide (including but not limited to about 0.0001% to about
0.05% lacosamide; about 0.0001% to about 5.0% lacosamide; about
0.05% to about 1.0% lacosamide; about 0.001% to about 0.05%
lacosamide; about 0.001% to about 5% lacosamide; about 0.5%
lacosamide to about 1% lacosamide; about 0.5% lacosamide; about
0.05% lacosamide; or about 5% lacosamide) may be used in the sodium
channel modulator delivery system (or sodium channel blocker
delivery system) described herein. Lacosamide may be used at
concentrations of less than about 5% (including but not limited to
about 0.001% to about 0.05% lacosamide; about 0.001% to about 5%
lacosamide; about 0.5% lacosamide; about 1% lacosamide; about 0.5%
lacosamide; about 0.05% lacosamide; or about 5% lacosamide) when it
is not used in the sodium channel modulator delivery system (or
sodium channel blocker delivery system) (i.e., when lacosamide is
delivered in eye drops, gels, ointments, etc. without using a
scleral lens).
[0076] In one embodiment, the sodium channel modulator includes a
solution containing about 0.001%, about 0.0015%, about 0.002%,
about 0.0025%, about 0.003%, about 0.0035%, about 0.004%, about
0.0045%, about 0.005%, about 0.0055%, about 0.006%, about 0.0065%,
about 0.007%, about 0.0075%, about 0.008%, about 0.0085%, about
0.009%, about 0.0095%, about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%,
about 3.5%, about 4.0%, about 4.5%, or about 5.0% lacosamide.
[0077] 5. Combinations
[0078] In some embodiments, the sodium channel blocker (or sodium
channel modulator) includes a combination of lacosamide and at
least one other sodium channel blocker. Non-limiting examples of
combinations of sodium channel blockers (or sodium channel
modulators) include lacosamide and bupivacaine, lacosamide and
lidocaine, lacosamide and proparacaine, lacosamide and flecainide,
lacosamide and tetracaine, lacosamide and ropivacaine, lacosamide
and levobupivacaine, lacosamide and flecainide, lacosamide and
carbamazepine, and lacosamide and amitriptyline. In some
embodiments, the total combined amount of sodium channel blockers
(or sodium channel modulators) in the solution is about 0.0005%,
about 0.001%, about 0.0015%, about 0.002%, about 0.0025%, about
0.003%, about 0.0035%, about 0.004%, about 0.0045%, about 0.005%,
about 0.0055%, about 0.006%, about 0.0065%, about 0.007%, about
0.0075%, about 0.008%, about 0.0085%, about 0.009%, about 0.0095%,
about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05%
of a sodium channel blocker (or sodium channel modulator). In some
embodiments, the total combined amount of sodium channel blockers
(or sodium channel modulators) in the solution is about 0.04% to
about 0.0005%, about 0.002% to about 0.001%, about 0.0019% to about
0.0009%, or about 0.02% to about 0.0025%. In some embodiments, the
sodium channel blocker delivery system (or sodium channel modulator
delivery system) includes a solution containing about 0.0001% to
about 0.05% of a sodium channel blocker and about 0.001% to about
0.5% of a sodium channel modulator.
[0079] In other embodiments, the method includes alternating
between lacosamide and at least one other sodium channel blocker
(or sodium channel modulator) at an alternation interval. The
alternation interval is the amount of time over which each sodium
channel blocker (or sodium channel modulator) is used for treatment
before switching to a different sodium channel blocker (or sodium
channel modulator). In one embodiment, the alternation interval is
one day, i.e., the patient is treated with lacosamide for one day,
then with a different sodium channel blocker (or sodium channel
modulator) for one day, then with lacosamide for one day, then with
the different sodium channel blocker (or sodium channel modulator)
for one day, and so on for the duration of treatment. In other
embodiments, the alternation interval is two days, three days, four
days, five days, six days, seven days, eight days, nine days, ten
days, eleven days, twelve days, thirteen days, or fourteen
days.
[0080] As will be apparent to one of ordinary skill in the art from
a reading of this disclosure, the embodiments of the present
disclosure can be embodied in forms other than those specifically
disclosed above. The particular embodiments described above are,
therefore, to be considered as illustrative and not restrictive.
Those skilled in the art will recognize, or be able to ascertain,
using no more than routine experimentation, numerous equivalents to
the specific embodiments described herein. The scope of the
invention is as set forth in the appended claims and equivalents
thereof, rather than being limited to the examples contained in the
foregoing description.
EXAMPLE 1
[0081] A patient with well established primary Sjogren's syndrome
and severe dry eyes was treated for intense, constant corneal pain
using the anesthetic delivery system disclosed herein.
Specifically, the patient was treated with bupivacaine and BOS-P
devices. The concentration of non-preserved bupivacaine was rapidly
titrated using frequent (every 2-5 minutes) drops in the more
symptomatic left eye (open label) measuring corneal sensitivity
with a Cochet-Bonnet aesthesiometer (with adequate recovery times)
until reaching the concentration that avoided any depression of
corneal sensitivity. The sub-anesthetic concentration in this
patient was determined to be 0.001%. Both BOS-P devices were filled
with 0.001% bupivacaine and inserted into the patient's eyes. The
patient then left.
[0082] The patient returned the next day volunteering that both
eyes felt more comfortable than they had been in 3 months. After
verifying the non-anesthetic effect of the 0.001% bupivacaine
concentration using sequential drops in her left eye, the reservoir
of the left lens was filled with non-preserved bupivacaine, and the
absence of depressed corneal sensitivity was periodically verified
during the day. At day's end, the patient reported the virtual
absence of pain in either eye. The patient reported little or no
pain after exposure to glass cleaner or a white board marker in the
examining room, which would ordinarily trigger severe pain. The
patient was given a vial of 0.01% bupivacaine to dilute 1:10 (e.g.,
add one drop of 0.01% bupivacaine to nine drops of saline) to fill
the reservoir of the left lens prior to inserting it the next
morning.
[0083] The next day, the patient reported virtually no pain in
either eye with the Visual Analog Scale. She wore the BOS-P
containing 0.001% bupivacaine in her left eye, and the BOS-P
containing saline in her right eye unmasked to the patient and
doctor, for about 8 hours. At that time she again reported
virtually no pain in either eye, even though the right eye was not
treated with bupivacaine. The lenses were removed and there was no
significant fluorescein staining in either eye. Corneal sensation
in the treated eye was normal.
EXAMPLE 2
[0084] After upper and lower cosmetic lid surgery in both eyes, a
patient suffered from corneal exposure and desiccation of her
corneas associated with severe chronic eye pain and disabling
photosensitivity that persisted after her corneas healed. Symptoms
were somewhat lessened after she was fitted with a BOS-P scleral
lens for each eye, but remained sufficiently severe so that she was
unable to read for more than 1-2 minutes.
[0085] The fluid compartments of both BOS-P lenses were filled with
non-preserved bupivacaine at a concentration of 0.002%, and the
BOS-P lenses with bupivacaine were worn at least 12 hours/day. Over
several weeks, all eye symptoms (e.g., photosensitivity, burning
pain, inability to read) resolved while corneal sensation remained
intact as documented by Cochet-Bonnet aesthesiometry. Eye symptoms
were also resolved after the bupivacaine was diluted to
0.0014%.
EXAMPLE 3
[0086] A patient suffered from Stevens-Johnson syndrome for about
25 years, complicated by scarring of the lids and corneas of both
eyes. The patient was fitted with scleral lens with marked
mitigation of eye pain for 2 years following which the patient
experienced increasingly disabling eye pain and photosensitivity
that was refractory to all available treatments and required high
daily doses of opioids to control. Three drops of ropivacaine 0.04%
were mixed with 5 drops of saline in the reservoirs of both of the
patient's scleral lenses, yielding a solution of 0.015%
ropivacaine. Following application of the scleral lenses containing
ropivacaine to the patient's eyes, the patient reported a rapid
mitigation of eye pain and photosensitivity.
[0087] The patient returned the following day 2 hours after
inserting the scleral lenses containing 0.015% ropivacaine. The
patient reported having worn the lenses until midnight the previous
day with total resolution of eye pain and photophobia. The patient
was free of symptoms at the time of examination. The patient's eyes
showed no adverse effects from the treatment, and corneal
sensitivity was normal as measured by the Cochet-Bonnet
aesthesiometer. The patient continued to report significant
mitigation of eye pain and photophobia and normal corneal
sensitivities without adverse treatment-related complications at
subsequent examinations.
EXAMPLE 4
[0088] A patient suffered from severe corneal neuropathic pain for
many years, greatly limiting the patient's quality of life. This
disease was refractory to previous treatments. Lacosamide was
placed in the fluid reservoir of the device where it remained in
contact with the cornea while it was worn (approximately 10
hours/day). Titration indicated that the maximum concentration that
avoided significant depression of corneal sensation was 0.003% and
this concentration was used in the fluid reservoir of the BOS-P.
This significantly mitigated the patient's corneal neuropathic pain
without any detrimental effects to the corneas, as determined by
slit lamp examination and confocal microscopy.
EXAMPLE 5
[0089] Eye drops containing 0.5% lacosamide were administered to
the eyes of two patients and to the an eye of the inventor. The
0.5% lacosamide solution did not depress corneal sensation in any
eye to which the 0.5% lacosamide solution was administered. The
0.5% lacosamide solution provided complete resolution of corneal
neuropathic pain in both patients almost immediately after
administration. The effect lasted over four hours in one patient
and over two hours in the other patient. Therefore, it is believed
that lacosamide may be used in eye drops at a concentration of up
to 5% to treat corneal neuropathic pain without depressing corneal
sensation.
EXAMPLE 6
[0090] A 39 year old patient underwent a bone marrow stem cell
transplant for leukemia and subsequently developed severe dry eyes
secondary to chronic graft versus host disease. She was fitted with
a scleral lens that eliminated the severe burning pain in her right
eye but continued to experienced knife-like and severe aching pain
in her left eye and disabling photosensitivity while wearing the
scleral lens. This persisted for 15 months. All eye and co-morbid
pain symptoms disappeared when the lens was worn with its fluid
reservoir filled with sterile, non-preserved lacosamide 0.05%.
* * * * *